Kinesin-I is a molecular motor that plays an essential role in the trafficking of subcellular components. It is generally thought that the majority of the kinesin in the cell is in a compact, inactive, soluble state, not associated with cargo or microtubules. It has been shown that the association of kinesin with any of a number of artificial cargoes (e.g. glass beads) results in activation of the motor protein, although until recently, it was unclear how kinesin was linked to its cargoes in vivo. A number of proteins have been identified which appear to link the motor to a number of cargoes. Included in these proteins is the Amyloid Precursor Protein. The identification of these physiological cargoes of kinesin provides a relevant transport substrate to characterize, and with which to test the hypothesis that cargo binding to kinesin results in the activation of motor function. Thus, the goal of this proposal is to analyze, structurally and functionally, kinesin-receptor interactions. First, the sequences of the cargo receptor proteins that bind kinesin will be characterized, and mutations that disrupt this interaction will be generated. A series of biochemical experiments examines the hypothesis that cargo association activates kinesin function. And finally, competition and localization experiments address the requirements for kinesin-receptor association in vivo. These experiments analyze, structurally and functionally, kinesin-receptor interactions.